Alzheimer's disease (AD) is a progressive neurodegenerative disorder, neuropathologically characterized by the presence of amyloid plaques and by the build-up of soluble oligomers of the amyloid-b peptide (Ab) in the brains of affected individuals. Current evidence supports the notion that Ab oligomers play a major role in neuronal dysfunction and neurotoxicity in AD. However, the mechanisms involved in the deleterious actions of Ab remain to be fully elucidated. A major unknown is the identity of the neuronal receptors that mediate the neuronal impact of Ab oligomers. With the goal of identifying such receptors, we have used phage display of peptide libraries to identify peptides that bind Ab oligomers. Using this approach, we have isolated four cysteine-linked heptapeptides that bind Ab and are highly homologous to different subunits of human NMDA receptors (NMDAr). Interestingly, memantine, a drug that was recently approved for AD treatment, is a moderate affinity NMDAr antagonist. Moreover, although several reports have shown that NMDAr are involved in Ab-induced excitotoxicity and in other aspects of AD, such as inhibition of long term potentiation, direct binding of Ab to NMDAr has not been demonstrated. Here we show that, in retinal neuronal cultures, Ab oligomers block the release of g-aminobutyric acid (GABA) triggered by NMDAr activation and all four peptides isolated by phage display prevent this effect. Our data indicate that Ab binds to NMDAr at regions that are homologous to the four selected peptides. Furthermore, these results suggest that these new Ab ligand peptides may be leads for the development of novel drugs to block the impact of Ab oligomers on NMDAr function in AD.

Supported by CNPq, FAPERJ and Howard Hughes Medical Institute